A novel series of benzimidazole NR2B-selective NMDA receptor antagonists

Davies, D. J. G.; Crowe, Matthew; Lucas, Nolwenn; Quinn, Joanna; Miller, David D.; Pritchard, Sara; Grose, David; Bettini, Ezio; Calcinaghi, Novella; Virginio, Caterina; Abberley, Lee; Goldsmith, Paul; Michel, Anton D.; Chessell, Iain P.; Kew, James N.C.; Miller, Neil D.; Gunthorpe, Martin J.

doi:10.1016/j.bmcl.2012.01.108

Cited by 15 publications

(8 citation statements)

References 26 publications

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“…101,606 (Chenard et al, 1995), radiprodil (Mullier et al, 2017), Merck-20j, andMK-0657 (Liverton et al, 2007;Addy et al, 2009) (Table 10). Alternative scaffolds include propanolamines (Tahirovic et al, 2008), benzimidazoles (McCauley et al, 2004;Davies et al, 2012), cyclic benzamidines (Nguyen et al, 2007), amino cyclopentanes (Layton et al, 2011), piperidinyl pyrrolidinones (Marcin et al, 2018), and other compounds (Claiborne et al, 2003;McIntyre et al, 2009;Mosley et al, 2009;Brown et al, 2011;Beinat et al, 2014;Buemi et al, 2014;Bristow et al, 2017;Dey et al, 2018;Thum et al, 2018;Zscherp et al, 2018;Zampieri et al, 2019;Zhang et al, 2019). Molecules with two aromatic rings separated by a linker also cross over to act selectively on GluN2B, including the dopamine receptor antagonist haloperidol, the r and dopamine receptor antagonist trifluperidol, the H 3 histamine receptor antagonists clobenpropit and iodophenpropit, the b-adrenergic receptor agonist nylidrin, and the TRPV1 receptor antagonist capsazepine (Supplemental Table 13).…”

Section: B Nmda Receptor Modulatorsmentioning

confidence: 99%

Structure, Function, and Pharmacology of Glutamate Receptor Ion Channels

Hansen¹,

Wollmuth²,

Bowie³

et al. 2021

Pharmacol Rev

375

445

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Section: B Nmda Receptor Modulatorsmentioning

confidence: 99%

Structure, Function, and Pharmacology of Glutamate Receptor Ion Channels

Hansen¹,

Wollmuth²,

Bowie³

et al. 2021

Pharmacol Rev

375

445

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“…Since the discovery of GluN2B-selective antagonists, numerous scaffolds of highly selective GluN2B NMDA receptor antagonists have been reported (reviewed by Layton et al, 2006;Mony et al, 2009;Koller and Urwyler, 2010;Ruppa et al, 2012). These include phenethanolamines such as ifenprodil (Williams, 1993), eliprodil (Carter et al, 1988), radiprodil (Michel et al, 2014;Auvin et al, 2020), traxoprodil (Chenard et al, 1995), Ro 25-6981 (Fischer et al, 1997), MK-0657 (Addy et al, 2009), plus additional scaffolds including propanolamines (Yuan et al, 2015), benzimidazoles (McCauley et al, 2004;Davies et al, 2012), cyclic benzamidines (Nguyen et al, 2007), amino cyclopentanes (Layton et al, 2011), piperidinyl pyrrolidinones (Marcin et al, 2018), and other compounds (Mosley et al, 2009;McIntyre et al, 2009;Brown et al, 2011;Buemi et al, 2014;Dey et al, 2018;Thum et al, 2018). Whereas crystallographic evaluation of ifenprodil at the GluN1/GluN2B heterodimer amino terminal domain (ATD) interface (Karakas et al, 2014) is the likely pose for many GluN2B-selective inhibitors, recent structural data revealed a unique region within the binding cavity that can be occupied by compounds with a more compact scaffold (Kemp and Tasker, 2009;Stroebel et al, 2016).…”

Section: Introductionmentioning

confidence: 99%

A Glutamate N-Methyl-d-Aspartate (NMDA) Receptor Subunit 2B–Selective Inhibitor of NMDA Receptor Function with Enhanced Potency at Acidic pH and Oral Bioavailability for Clinical Use

Myers

Ruppa

Wilson

et al. 2021

J Pharmacol Exp Ther

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We describe a clinical candidate molecule from a new series of GluN2B-selective inhibitors that shows enhanced inhibition at extracellular acidic pH values relative to physiological pH. This property should render these compounds more effective inhibitors of NMDA receptors at synapses responding to a high frequency of action potentials, since glutamate-containing vesicles are acidic within their lumen. In addition, acidification of penumbral regions around ischemic tissue should also enhance selective drug action for improved neuroprotection. The aryl piperazine we describe here shows strong neuroprotective actions with minimal side effects in preclinical studies. The clinical candidate molecule, NP10679, has high oral bioavailability with good brain penetration, and is suitable for both intravenous and oral dosing for therapeutic use in man. SIGNIFICANCEThis study identifies a new series of GluN2B-selective negative allosteric modulators with properties appropriate for clinical advancement. The compounds are more potent at acidic pH associated with ischemic tissue, and this property should increase the therapeutic safety of this class by improving efficacy in affected tissue while sparing NMDA receptor block in healthy brain.

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“…Both NR2A and NR2B were shown to have distinct pharmacology and a role in the regulation of NMDAR, and have been suggested to be differentially involved in the mechanisms of learning and emotionality (Fleischmann et al, 2003;Li & Tsien, 2009). A body of evidence has demonstrated the involvement of NR2A, NR2B and NR1 subunits in the neurobiology of neuropsychiatric conditions such as anxiety, psychosis, impulsivity, Alzheimer's disease and major depression (Davies et al, 2012;Geissler & Lesch, 2011;Tsang et al, 2008).…”

Section: Introductionmentioning

confidence: 99%

Altered emotionality, hippocampus-dependent performance and expression of NMDA receptor subunit mRNAs in chronically stressed mice

Costa-Nunes

Зубарева

Araújo-Correia

et al. 2013

Stress

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N-Methyl-D-aspartate receptor (NMDAR)-mediated neurotransmission in the hippocampus is implicated in cognitive and emotional disturbances during stress-related disorders. Here, using quantitative RT-PCR, we investigated the hippocampal expression of NR2A, NR2B and NR1 subunit mRNAs in a mouse stress paradigm that mimics clinically relevant conditions of simultaneously affected emotionality and hippocampus-dependent functions. A 2-week stress procedure, which comprised ethologically valid stressors, exposure to a rat and social defeat, was applied to male C57BL/6J mice. For predation stress, mice were introduced into transparent containers that were placed in a rat home cage during the night; social defeat was applied during the daytime using aggressive CD1 mice. This treatment impaired hippocampusdependent performance during contextual fear conditioning. A correlation between this behavior and food displacement performance was demonstrated, suggesting that burrowing behavior is affected by the stress procedure and is hippocampus-dependent. Stressed mice (n ¼ 22) showed behavioral invigoration and anomalous anxiolytic-like profiles in the O-maze and brightly illuminated open field, unaltered short-term memory in the step-down avoidance task and enhanced aggressive traits, as compared to non-stressed mice (n ¼ 10). Stressed mice showed increased basal serum corticosterone concentrations, hippocampal mRNA expression for the NR2A subunit of the NMDAR and in the NR2A/NR2B ratio; mRNA expression of NR2B and NR1 was unchanged. Thus, stress-induced aberrations in both hippocampal-dependent performance and emotional abnormalities are associated with alterations in hippocampal mRNA NR2A levels and the NR2A/NR2B ratio and not with mRNA expression of NR2B or NR1.

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A novel series of benzimidazole NR2B-selective NMDA receptor antagonists

Cited by 15 publications

References 26 publications

Structure, Function, and Pharmacology of Glutamate Receptor Ion Channels

Structure, Function, and Pharmacology of Glutamate Receptor Ion Channels

A Glutamate N-Methyl-d-Aspartate (NMDA) Receptor Subunit 2B–Selective Inhibitor of NMDA Receptor Function with Enhanced Potency at Acidic pH and Oral Bioavailability for Clinical Use

Altered emotionality, hippocampus-dependent performance and expression of NMDA receptor subunit mRNAs in chronically stressed mice

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